Carcinomas arise in a complex microenvironment consisting of multiple distinct epithelial lineages of the parenchyma surrounded by the mesenchyme, stromal fibroblasts, vasculature, and immune cells. It is not known what cell type cancers arise from. We rely on mouse models to prospectively examine early oncogenic events since it is not feasible to study initiation events in human. However, most transgenic mouse models are not cell type specific. We hypothesize that different epithelial subtypes have varied susceptibility for tumor initiation. Since most solid human tumors harbor aberrations in the Rb cell cycle regulatory pathway, we tested the susceptibility of two epithelial subtypes expressing cytokeratin (K) 18 or K19 to the disruption of Rb and its family members p107 and p130 tumor suppression (Rb-TS, collectively) in vivo. We found that tumorigenesis could be initiated in either K18 or K19 cells. However, the susceptibility of epithelial tissues to Rb-TS inactivation was subtype-dependent. For bladder, stomach, lung, and colon epithelium, K19 cells were more susceptible to Rb-TS inactivation, while for thymic epithelium, K18 cells. Moreover, when Rb-TS was inactivated in K19 cells, males had early onset of bladder adenoma compared to females (9 vs 14 months post induction), and only small percentage of animals developed carcinoma/adenocarcinoma, indicating that other genetic event(s) is required for tumor progression. To further assess the susceptibility of prostate epithelium to Rb-TS inactivation, we inactivated Rb-TS in K18 and K19 subtypes in prostate using prostate specific Cre line (Pb-Cre4). To our surprise, mouse prostatic intraepithelial neoplasia (mPIN) lesions were initiated in K19 cells, but not in K18 cells at 2 months of age, indicating that K19 cells are more susceptible to prostate tumorigenesis. Thus, cell subtype tumors are initiated in dictates the histopathological phenotype and onset of tumor development. We are currently in the process of writing up the 1st manuscript and analyzing the mouse prostate phenotype developed in K18 or K19 transgenic mice with Pten deletion. We are also assessing the tumors response to castration in these models. Song Y, Yang C, Pan W, Fathalizadeh A, Lu X, Gilbert D, Wang C, O?Sullivan N, Haines D, Martin P, Van Dyke T. Rb inactivation in epithelial subtypes: Differential susceptibility for tumor initiation. (in preparation)